The specific aims of this project during the request period of funding are as follows: (a) the preparation and evaluation of both enantiomers of 5-, 6- and 2'-analogues of 3'-thia-2'-deoxycytidine (BCH-189,3TC) as potential inhibitors of HIV; (b) the development of an efficient, large-scale synthesis for (+)-5-fluorodioxolane C (FDOC); (c) the preparation and evaluation of other heterocyclic nucleoside analogues, including dioxolanes, dithiolanes, oxathiolanes, imidazolanes, oxazolanes and thiazolanes as potential inhibitors of HIV; (d) the preparation and evaluation of "L"-nucleosides, such as L-D4C, as potential low toxicity inhibitors of HIV: and (e) the development of nucleoside analogues which exhibit selective cytotoxicity for HIV-infected cells. Several of the compounds described in this proposal have already been shown to be very potent anti-HIV agents. In particular, 3TC, which is the subject of several large scale HIV and HBV clinical trials, as well as our compound, (-)-FTC (which appears to be superior to 3TC, especially with regard to its apparent lack of any significant bone marrow toxicity) which should be entering clinical trials in the very near future. Several other compounds which are highlighted here appear quite promising, not only as leads but also from the information we will learn from their preparation and evaluation. Since the research proposed here could lead to the discovery and development of several clinically-important anti-AIDS agents, we feel strongly that it is worthy of the continued support NIH.